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(12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain Et Al US 2012O190743A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain et al. (43) Pub. Date: Jul. 26, 2012 (54) COMPOUNDS FOR TREATING DISORDERS Publication Classification OR DISEASES ASSOCATED WITH (51) Int. Cl NEUROKININ 2 RECEPTORACTIVITY A6II 3L/23 (2006.01) (75) Inventors: Jerald Bain, Toronto (CA); Joel CD7C 69/30 (2006.01) Sadavoy, Toronto (CA); Hao Chen, 39t. ii; C Columbia, MD (US); Xiaoyu Shen, ( .01) Columbia, MD (US) A6IPI/00 (2006.01) s A6IP 29/00 (2006.01) (73) Assignee: UNITED PARAGON A6IP II/00 (2006.01) ASSOCIATES INC., Guelph, ON A6IPI3/10 (2006.01) (CA) A6IP 5/00 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 13/394,067 A6IP 25/30 (2006.01) A6IP5/00 (2006.01) (22) PCT Filed: Sep. 7, 2010 A6IP3/00 (2006.01) CI2N 5/071 (2010.01) (86). PCT No.: PCT/US 10/48OO6 CD7C 69/33 (2006.01) S371 (c)(1) (52) U.S. Cl. .......................... 514/552; 554/227; 435/375 (2), (4) Date: Apr. 12, 2012 (57) ABSTRACT Related U.S. Application Data Compounds, pharmaceutical compositions and methods of (60) Provisional application No. 61/240,014, filed on Sep. treating a disorder or disease associated with neurokinin 2 4, 2009. (NK) receptor activity. Patent Application Publication Jul. 26, 2012 Sheet 1 of 12 US 2012/O190743 A1 LU 1750 15OO 1250 OOO 750 500 250 O O 20 3O 40 min SampleName: EM2OO617 Patent Application Publication Jul. 26, 2012 Sheet 2 of 12 US 2012/O190743 A1 kixto CFUgan <tro CFUgan FIG.2 Patent Application Publication Jul. 26, 2012 Sheet 3 of 12 US 2012/O190743 A1 <>ClCDIS (ILu/5n.)Luo?euqu<><>Luo £C"GOI– OL–FHizº"SG) OGC)I ZESC;L"iz L–E.L.Z-EL£CL.tv-EIL Percent Specific Binding Patent Application Publication Jul. 26, 2012 Sheet 4 of 12 US 2012/0190743 A1 120 OO 8O % 60 I 40 20 O 25 5 65 15 1355 155 16 7 186 19 Control Fraction FIG. 4 Patent Application Publication Jul. 26, 2012 Sheet 5 of 12 US 2012/O190743 A1 UPA 171060309 2. Diode Array 352 2O Range: 7996e-2 50e-2 4.5e-2 3.5e-2 3.0e-2 25e-2 20e-2 1.5e-2 10e-2 50e-3 OO Time FIG.5 OOO CO 2 OO 3 OO 4.OO 5.OO 600 TCO 800 900 OOO Patent Application Publication Jul. 26, 2012 Sheet 6 of 12 US 2012/O190743 A1 UPA 185060309 2. Dioce Array 352 210 38e-2 Range 5552e2 36e-2 34e-2 32e-2 30e-2 28e-2 26e-2 24-2 22e-2 20e-2 8e-2 6e-2 14e-2 2e-2 Oe-2 80e-3 60e-3 40e-3 20e-3 O. OO Time FIG. 6 OOO OO 2 OO 3 OO 4.OO 5 OC 600 700 800 900 OOO Patent Application Publication Jul. 26, 2012 Sheet 7 of 12 US 2012/O190743 A1 UPA 171060309 2. Diode Array 3.53 190 Range:2.195e-2 1.0e-2 90e-3 8.0e-3 70e-3 60e-3 D K 50-3 3.0e-3 0.22 2038 135 Oe-3 .." 385 OO , Time FIG.7 OOO OO 2 OO 3 OO 4.OO 5 OO GOO 7 OO 8 OO 9 OC O.OO Patent Application Publication Jul. 26, 2012 Sheet 8 of 12 US 2012/O190743 A1 UPA 18S 060309 3.53 2. Diode Array 5.5e-3 190 Range: 1831e-2 5.0e-3 4.5e-3 40e-3 3.5e-3 30e-3 D g 25e-3 20e-3 15e-3 O77 Oe-3 O38 OSO 4.5 18O 6.0e-4 240 OO Time FIG.8 OOO CO 2 OO 3 OO 400 500 6 OO 7 OO 800 900 OOO Patent Application Publication Jul. 26, 2012 Sheet 9 of 12 US 2012/O190743 A1 ElL. -tz-EIL <>CdO.IS $EZ"O L—9%,ZAO- KOE-EIL 9-E.L._/—EIL OL–EILILE:—E.L. O£ Ozae OzL OL Oiz5 OZ Percent Specific Binding Patent Application Publication Jul. 26, 2012 Sheet 10 of 12 US 2012/O190743 A1 -E.L. tz-EIL <>CloIs ©–EIL S»—E.L.„V–L. OLTOEDI– €S-EºSÐ~L€S-E6L SB-Eºº^65G-EAZLC º—E.IL€S-EIL ID>|OGOI OL-EIL|-E.L.Z– Percent Specific Binding Patent Application Publication Jul. 26, 2012 Sheet 11 of 12 US 2012/O190743 A1 g N S Y (N () Z $ $ () () () K ) () O O O O O O O O (N O N O (N (N % Maximum Response (RFU) Patent Application Publication Jul. 26, 2012 Sheet 12 of 12 US 2012/O190743 A1 H)- s HH Y - 9 (N i : N. V. OE Z$S $28 3. S is g g to () ;O : T () () () L K ) O ) O ) O O C () O) (N O N () (N (N % Maximum Response (RFU) US 2012/O 190743 A1 Jul. 26, 2012 COMPOUNDS FORTREATING DSORDERS plex interplay of etiological factors including the role of OR DISEASES ASSOCATED WITH second messengers mediating membrane bound and intrac NEUROKININ 2 RECEPTOR ACTIVITY ellular processes. This has led to investigation of hormonal pathways Such as the hypothalamic-pituitary-adrenal (HPA) CROSS-REFERENCE TO RELATED axis (the activity of which is elevated in 20-40% of commu APPLICATIONS nity-dwelling patients with major depressive disorder), thy 0001. This application claims the benefit of U.S. Provi roid axis (5-10% of patients evaluated with major depressive sional Application No. 61/240,014, filed Sep. 4, 2009, which disorder have previously undetected thyroid dysfunction), is hereby incorporated by reference. growth hormone, prolactin, testosterone and the role of inflammatory processes and their markers such as interleu FIELD OF THE INVENTION kin-1 and -6 and tumour necrosis factor. 0002 The invention relates to compounds, pharmaceuti 0008 Most people with major depressive disorder experi cal compositions and methods for treating disorders or dis ence some degree of symptom return, and 20-30% exhibit a eases associated with neurokinin 2 (NK) receptor activity. chronic course (defined as a syndromal level of depressive symptom severity for two years or more (Treatment of BACKGROUND OF THE INVENTION Chronic Depression (Editorial))). Depressive Mood Disorders 0009 All depressed people require continuation of phar macotherapy to permit recovery and prevent relapse. A Sub 0003. Depressive mood disorders are a group of mood stantial proportion of depressed patients require maintenance disorders characterized by feelings of depression. Depressive pharmacotherapy to prevent recurrence and further consoli mood disorders include major depressive disorder, dysthymic date psychosocial recovery. However, while one of the major disorder, depressive phase of bipolar disorder, depression due factors in effective antidepressant therapy is maintaining the to a general medical condition Such as depression associated patient on an adequate dose of medication for an adequate with dementia or schizoaffective disorder, substance-induced depression, postpartum depression and seasonal affective dis duration, this is often difficult. Many patients fear taking order. current antidepressants because of real or imagined physical 0004 Major depressive disorder (also known as major effects. Some patients prefer to use so-called natural health depression, clinical depression, unipolar depression and uni promoting Substances and non-pharmacological interven polar disorder) is very prevalent in the general population. tions. Patients who are prepared to take antidepressants often Recent North American data show a 14.5% lifetime risk of encounter a wide array of side effects, which leads them to be major depression in adults and 8.1% one year prevalence non-compliant or to reject therapy entirely. Selective seroto (Results from the 2004 National Survey on Drug Use and nin reuptake inhibitors (SSRI) for example, commonly Health: National findings: Revisions as of Sep. 8, 2005; induce gastrointestinal upset, headaches, sleep disturbance Department of Health and Human Services. Substance Abuse and significant sexual impairments among many other side and Mental Health Services Administration Office of Applied effects. Most antidepressants have at least some significant Studies). side effects and these limit clinicians capacity to effectively 0005. The mean duration of a depressive episode with treat many patients. modern treatments is about 16 weeks, although some data 0010 Major depressive disorder can be associated with Suggest alonger duration of about 6-8 months, far less than in other disorders and/or syndromes, including disorders of the the pre-antidepressant therapy era when the duration was brain or nervous system, anxiety disorder (which includes about 18 months (Kendler, McLeod, Patten). generalized anxiety disorder, panic disorder, phobias, obses 0006 Antidepressants have had some impact on the treat sive-compulsive disorder, post-traumatic stress disorder, ment of major depressive disorder and on reducing the Suf separation anxiety, social anxiety disorder, otherwise known fering of patients. Not all of the impact has been positive. as Social phobia, bipolar disorder, and dementia); sexual dys Patients with major depressive disorder are often impaired in function; Substance abuse, eating disorders and hormone dis function and frequently have co-morbid disorders such as orders, such as thyroid dysfunction, hypogonadism, meno Substance abuse that can be attributed to the underlying major depressive disorder. Major depressive disorder leads to pause, etc. Treatment of the major depressive disorder often increased utilization of health services and can have a devas leads to improvement in these related disorders and Syn tating impact on Social structure and Societal economics. dromes. 0007. The cause of major depressive disorder is not fully 0011. In addition, some therapeutic agents used to treat known. Disturbance of monoamine synthesis and activity has depression are also effective in treating other conditions. For been a prominent etiological theory of major depressive dis example, antidepressants have been demonstrated to be effec order for the past few decades and support for this has been tive in the treatment of hot flashes associated with meno strengthened by the effectiveness of medications that enhance pause, pain and Smoking cessation.
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